Polyphenols are an incredibly diverse group of compounds (Ferriera et al., Tetrahedron, 48: 10, 1743-1803, 1992). They widely occur in a variety of plants, some of which enter into the food chain. In some cases they represent an important class of compounds for the human diet. Although some of the polyphenols are considered to be non-nutritive, interest in these compounds has arisen because of their possible beneficial effects on health. For instance, quercetin (a flavonoid) has been shown to possess anticarcinogenic activity in experimental animal studies (Deshner et al., Carcinogenesis, 7: 1193-1196, 1991: and Kato et al., Carcinogenesis, 4, 1301-1305 1983). (+)-catechin and (−)-epicatechin (flavan-3-ols) have been shown to inhibit Leukemia virus reverse transcriptase activity (Chu et al., J. of Natural Prod., 55: 2, 179-183, 1992). Nobotanin (an oligomeric hydrolyzable tannin) has also been shown to possess anti-tumor activity (Okuda et al., presented at the XVIth International Conference of the Groupe Polyphenols, Lisbon, Portugal, Jul. 13-16, 1992). Procyanidin oligomers have been reported by the Kikkoman Corporation for use as antimutagens (JP 04190774A, Jul. 7, 1992).
Some polyphenol, such as B-type procyanidins have been shown to have a beneficial effect on nitric oxide (NO) release and hence on treatment of a variety of health conditions that positively respond to NO (see e.g. U.S. Pat. No. 6,670,390 to Romanczyk et al.).
Nitric oxide (NO) is known to inhibit platelet aggregation, monocyte adhesion and chemotaxis, and proliferation of vascular smooth muscle tissue which are critically involved in the process of atherogenesis. The concentration of NO can be reduced in atherosclerotic tissues due to its reaction with oxygen free radicals. The loss of NO due to these reactions leads to increased platelet and inflammatory cell adhesion to vessel walls to further impair NO mechanisms of relaxation. In this manner, the loss of NO may promote atherogenic processes, leading to progressive disease states.
Hypertension is a condition where the pressure of blood as it circulates within the blood vessels is higher than normal. When the systolic pressure exceeds 150 mm Hg or the diastolic pressure exceeds 90 mm Hg for a sustained period of time, damage is done to the body. Hypertension is a leading cause of vascular diseases, including stroke, heart attack, heart failure, and kidney failure. For example, excessive systolic pressure can rupture blood vessels anywhere. In cases when a rapture occurs within the brain, a stroke results. Hypertension can also cause thickening and narrowing of the blood vessels which can lead to atherosclerosis. Elevated blood pressure can also force the heart muscle to enlarge as it works harder to overcome the elevated resting (diastolic) pressure when blood is expelled. This enlargement can eventually produce irregular heart beats or heart failure. Hypertension is called the “silent killer” because it causes no symptoms and can only be detected when blood pressure is checked.
The regulation of blood pressure is a complex event where one mechanism involves the expression of constitutive Ca+2/calmodulin dependent form of nitric oxide synthase (NOS), known as endothelial nitric oxide synthase or eNOS. NO produced by this enzyme produces smooth muscle relaxation in the vessel (dilation), which lowers the blood pressure. When circulating concentrations of NO are reduced, either because production is blocked by an inhibitor or in pathological states, such as atherosclerosis, the vascular muscles do not relax to the appropriate degree. The resulting vasoconstriction increases blood pressure and may be responsible for some forms of hypertension.
Given the large number of people suffering from hypertension and related diseases and disorders of the vascular system, there is considerable interest in finding therapeutic ways to maintain the NO pool at its normal, healthy levels. Pharmacological agents capable of releasing NO, such as nitroglycerin or isosorbide dinitrate, remain mainstays of vasorelaxant therapy. Applicants have now surprisingly discovered that A-type procyanidins can be utilized for preserving the NO pool, inducing vasorelaxation and/or treating and/or preventing NO-responsive diseases and disorders.